Abstract
PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.
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Acknowledgements
We thank the patients and their parents for participating in this study. We are grateful to Arif Ekici, Steffen Uebe, and Mandy Krumbiegel for support with the SNP arrays and whole exome sequencing, Farah Radwan, Angelika Diem, and Petra Rothe for excellent technical assistance, as well as Oliver Rompel for examining the MRI images. We thank Charis Eng and Stefan Aretz for helpful discussions and sharing unpublished results. This study was supported by grants from the Deutsche Forschungs-gemeinschaft to RAJ (AB393/2-2) and by Cancer Research UK grant number C38302/A12278, through the Oxford Cancer Research Centre Development Fund (OCRC0612-HU) to HHU. HHU and HC declare industry collaboration via the Oxford UCB target program.
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Schwerd, T., Khaled, A., Schürmann, M. et al. A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome. Eur J Hum Genet 24, 889–894 (2016). https://doi.org/10.1038/ejhg.2015.209
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DOI: https://doi.org/10.1038/ejhg.2015.209
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